GENETIC EPIDEMIOLOGY OF ESOPHAGEAL CANCER

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The current view on the etiology of esophageal cancer (EC) largely favors environmental factors, and is supported by the marked variation in the geographic distribution of the disease. However, some recent studies have suggested that EC is familial, and further that genetic susceptibility may also be important. However stronger evidence for genetic susceptibility and gene-environment-lifestyle interactions in the etiology of EC is needed. The purpose of the proposed study is to analyze data on EC mortality, incidence and the measured risk factors: gender, other cancers, smoking history, alcohol consumption, eating of pickled vegetables, and eating of hot food. The data were collected on a cohort of 5039 multigenerational families from Yangcheng County, Shanxi Providence, China. the cohort was first established in 1979 and followed up in 1989. Detailed information on biologic relationships (pedigrees), age-of-onset, and risk factor information were collected in 592 families; these will be the main focus of the proposal. A database on the 5039 families has already been created at the Fox Chase Cancer Center. Funding is sought to perform and analysis that will assess the role of actual biologic relationships and risk factors in esophageal cancer. Furthermore, it will provide information that can be used to determine the motivation, and hypotheses and the inputs for designing further studies on environmental, lifestyle and genetic factors that make esophageal cancer familial. The Specific Aims are: 1) To assess familial aggregation and the role of measured risk factors in esophagel cancer taking into account biologic relationships; 2) To determine the distribution of and familial correlations in age-of-onset in esophageal cancer; 3) To perform segregation analysis to determine the possible involvement of an unmeasured major gene in the etiology of esophageal cancer; 4) To plan a follow-up study on the genetic epidemiology of esophageal cancer. The first three aims will be pursued simultaneously and completed within the first eight months of the funding period. the last four months of the funding period will be devoted to the fourth aim, which is to use the results of the analyses to design a more comprehensive study of environment, lifestyle and genetic factors in familial EC and to develop a grant application. The analytic framework is the regressive models which account for familial correlations by specifying a regression relationship between a person's phenotype and a set of explanatory variables including his genotype with response specific loci, the phenotypes of older relatives, and environmental and life-style covariates. The appeal of this method is that it simultaneously provides for the effects resulting from important gene(s) and those resulting from complex patterns of residual familial correlations, including sib-sib, spouse-spouse, and parent- offspring phenotypic correlations, without or with reference to explicit genetic or environmental causal mechanisms. Known mechanisms of carcinogenesis are incorporated by choosing suitable parameterization.